Journal
ONCOTARGET
Volume 8, Issue 62, Pages 105882-105904Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.22413
Keywords
renal oncocytoma; complex I deficiency; glutathione metabolism; mtDNA mutation
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Funding
- Max Planck Society
- BHI [TRG1.2.2]
- China Scholarship Council (CSC)
- Italian Association for Cancer Research (AIRC) [IG14242]
- Italian Ministry of Health ricerca finalizzata giovani ricercatori DISCO TRIP
- Worldwide Cancer Research UK grant DHOMOS
- National Institutes of Health [R01GM106019]
- Canadian Institutes of Health Research Operating [MOP-125952, RSN-124512, 132191]
- Canadian Institutes of Health Research Foundation [FDN-154318]
- CIHR [MSH-130178]
- Bundesministerium fur Bildung und Forschung [031L0057]
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Renal oncocytomas are rare benign tumors of the kidney and characterized by a deficient complex I (CI) enzyme activity of the oxidative phosphorylation (OXPHOS) system caused by mitochondrial DNA (mtDNA) mutations. Yet, little is known about the underlying molecular mechanisms and alterations of metabolic pathways in this tumor. We compared renal oncocytomas with adjacent matched normal kidney tissues on a global scale by multi-omics approaches, including whole exome sequencing (WES), proteomics, metabolomics, and metabolic pathway simulation. The abundance of proteins localized to mitochondria increased more than 2-fold, the only exception was a strong decrease in the abundance for CI subunits that revealed several pathogenic heteroplasmic mtDNA mutations by WES. We also observed renal oncocytomas to dysregulate main metabolic pathways, shunting away from gluconeogenesis and lipid metabolism. Nevertheless, the abundance of energy carrier molecules such as NAD+, NADH, NADP, ATP, and ADP were significantly higher in renal oncocytomas. Finally, a substantial 5000-fold increase of the reactive oxygen species scavenger glutathione can be regarded as a new hallmark of renal oncocytoma. Our findings demonstrate that renal oncocytomas undergo a metabolic switch to eliminate ATP consuming processes to ensure a sufficient energy supply for the tumor.
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